Pyrridinobenzodiazepines (PDDs) and benzopyrridodiazecines (BPDs) are related structures to pyrrolobenzodiazepines (PBDs). The pyrrolobenzodiazepines (PBDs) are a group of compounds some of which have been shown to be sequence-selective DNA minor-groove binding agents. The PBDs were originally discovered in Streptomyces species (1-5). They are tricyclic in nature, and are comprised of fused 6-7-5-membered rings that comprise an anthranilate (A ring), a diazepine (B ring) and a pyrrolidine (C ring) (3). They are characterized by an electrophilic N10=C11 imine group (as shown below) or the hydrated equivalent, a carbinolamine [NH—CH(OH)], or a carbinolamine alkyl ether ([NH—CH(OR, where R=alkyl)] which can form a covalent bond to a C2-amino group of guanine in DNA to form a DNA adduct (6).

The natural products interact in the minor groove of the DNA helix with excellent fit (i.e., good “isohelicity”) due to a right-handed longitudinal twist induced by a chiral C11a-position which has the (S)-configuration (6). The DNA adduct has been reported to inhibit a number of biological processes including the binding of transcription factors (7-9) and the function of enzymes such as endonucleases (10, 11) and RNA polymerase (12). PBD monomers (e.g., anthramycin) have been shown by footprinting (6), NMR (13, 14), molecular modeling (15) and X-ray crystallography (16) to span three base pairs and to have a thermodynamic preference for the sequence 5′-Pu-G-Pu-3′ (where Pu=purine, and G is the reacting guanine) (17) and a kinetic preference for Py-5-Py (where Py=Pyrimidine).
PBDs are thought to interact with DNA by first locating at a low-energy binding sequence (i.e., a 5′-Pu-G-Pu-3′ triplet) through Van der Waals, hydrogen bonding and electrostatic interactions (7). Then, once in place, a nucleophilic attack by the exocyclic C2-amino group of the central guanine occurs to form the covalent adduct (7). Once bound, the PBD remains anchored in the DNA minor groove, avoiding DNA repair by causing negligible distortion of the DNA helix (16). The ability of PBDs to form an adduct in the minor groove and crosslink DNA enables them to interfere with DNA processing and, hence, their potential for use as antiproliferative agents.
A number of monomeric PBD structures have been isolated from Streptomyces species, including anthramycin (18) the first PBD, tomamycin (19), and more recently usabamycin (20) from a marine sediment Streptomyces species in a marine sediment. This has led to the development of a large range of synthetic analogues which have been reviewed (1, 21). More recently, a number of monomeric PBD structures that are linked through their C8 position to pyrroles and imidazoles have been reported WO 2007/039752, WO 2013/164593 (22-27).
In addition to monomeric PBD structures, a large range of synthetic PBD dimers (i.e. two PBD structures linked via a spacer) have been developed. Early C7- and C8-linked examples (28, 29) were designed to span greater lengths of DNA than the PBD monomers, to have enhanced sequence-selectivity, and to form DNA cross-links that might be more difficult for tumour cells to repair. In particular, the C8 position of the A ring has been extensively utilized for the production of PBD dimers (29, 30). The synthesis of various PBD dimers has been reviewed (1, 21).
WO 2010/091150 discloses dimeric PBD derivatives linked via their aromatic A-rings, in particular, dimers of tetracyclic 6-7-5-6 ring systems. WO 2010/028850 also discloses a dimer of a 6-7-6 ring system linked via their A-rings. WO 2015/028850 discloses PBD dimers that are linked via phosphine oxide containing linkers attached to their aromatic A-rings. In addition, WO 2015/028850 discloses a compound containing a 6-7-6 ring system linked via the key phosphine oxide containing linkers.
Various PBDs have been shown to act as cytotoxic agents in vitro, for example, WO 00/12508, WO 2004/087711, and as anti-tumour in vivo in animal tumour models, for example, WO 2011/117882, WO 2013/164593. Furthermore, the C8/C8′-linked PBD dimer SJG-136 (29, 32) has completed Phase I clinical trials for leukaemia and ovarian cancer (31) and has shown sufficient therapeutic benefit to progress to Phase II studies.

However, results from a Phase I clinical evaluation of SJG-136 revealed that the drug produced several adverse effects including lower-limb edema and fatigue (33).
Thus, there exists a need for further compounds related to PBDs that are therapeutically active for treating a variety of proliferative diseases.
The present application reports pyrridinobenzodiazepines (PDDs) linked by the C-ring. PDDs are related to PBDs but contain an expanded 6-membered C-ring as compared to the 5-membered C-ring of PBDs. The present application also reports benzopyrridodiazecines (BPDs), which have an expanded 8-membered B-ring in addition to the expended 6-membered C-ring. The present invention seeks to alleviate or overcome problem(s) associated with the prior art.